Therapeutic compositions including spn10 and uses thereof

Abstract

Disclosed herein are methods and compositions for the treatment, prevention, inhibition, amelioration and/or delay in the onset of diseases, disorders and/or conditions comprising administration of SPN10 or an analogue thereof, alone or in combination with one or more additional active agents (e.g. active pharmaceutical ingredients), wherein SPN10 is the aromatic-cationic peptide, H-L-Trp-L-Arg-L-Trp-L-Lys-NH 2 , or a pharmaceutically acceptable salt, tautomer, hydrate, and/or solvate thereof.

1 . A composition comprising SPN10, or an analogue thereof, alone or in combination with one or more additional active agents, wherein SPN10 is the aromatic-cationic peptide H-L-Trp-L-Arg-L-Trp-L-Lys-NH 2 , or a tautomer, hydrate, solvate and/or pharmaceutically acceptable salt thereof. 
     
     
         2 . The composition of  claim 1 , wherein the one or more additional active agents is a peptide as described in Section II or other therapeutic agent(s) such as cyclosporine, a cardiac drug, an anti-inflammatory drug, an anti-hypertensive drug, a steroid, an antibiotic, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a beta blocker, and angiotensin II receptor blocker (ARB), an antibody, an ophthalmic drug, an antioxidant, a metal complexer, a metal chelator and/or an antihistamine. 
     
     
         3 . A method for treating, preventing, inhibiting, ameliorating or delaying the onset of a disease, disorder or condition, comprising administering a therapeutically effective amount of a composition comprising SPN10, or an analogue thereof, alone or in combination with one or more additional active agents, wherein SPN10 is the aromatic-cationic peptide, H-L-Trp-L-Arg-L-Trp-L-Lys-NH 2 , or a tautomer, hydrate, solvate and/or pharmaceutically acceptable salt thereof. 
     
     
         4 . The method of  claim 3 , wherein the disease, disorder or condition comprises a neurological or neurodegenerative disease or condition, cardiac ischemia, cerebral ischemia, ischemia reperfusion, hypoxia, atherosclerosis, ureteral obstruction, diabetes, burns or secondary effects of a burn, complications of diabetes, arthritis, liver damage, insulin resistance, diabetic nephropathy, acute renal injury, chronic renal injury, acute or chronic renal injury due to exposure to nephrotoxic agents and/or radiocontrast dyes, hypertension, metabolic syndrome, an ophthalmic disease or condition such as dry eye, dry age-related macular degeneration (AMD), wet age related macular degeneration (AMD), Leber Hereditary Optic Neuropathy (LHON), Dominant optic atrophy (DOA), diabetic retinopathy, cataracts, retinitis pigmentosa, glaucoma, macular degeneration, choroidal neovascularization, retinal degeneration or oxygen-induced retinopathy, Barth Syndrome, Alport Syndrome, Alpers Syndrome, Leigh Syndrome, Myoclonic Epilepsy and Ragged-Red Fiber Disease (MERRF), Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like Episodes (MELAS), Pearson Syndrome, Polymerase gamma (POLG) mutations, Sengers Syndrome, Barth cardiomyopathy, cardiomyopathy, ischemic heart disease, heart failure, hypertensive cardiomyopathy, hypertrophic cardiomyopathy, vessel occlusion, vessel occlusion injury, myocardial infarction, coronary artery disease, oxidative damage, long chain fatty acid oxidation disorder, a tauopathy, a TDP-43 proteinopathy or an α-synucleiopathy. 
     
     
         5 . The method of  claim 3 , wherein the disease, disorder or condition comprises mitochondrial permeability transition. 
     
     
         6 . The method of  claim 4 , wherein the neurological or neurodegenerative disease or condition comprises Friedreich's ataxia (FA), Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), Multiple Systems Atropy (MSA) or Multiple Sclerosis (MS). 
     
     
         7 . The method of  claim 3 , wherein a subject is suffering from ischemia or has an anatomic zone of no-reflow in one or more of cardiovascular tissue, skeletal muscle tissue, cerebral tissue and renal tissue. 
     
     
         8 . (canceled) 
     
     
         9 . A method for treating, preventing, inhibiting, ameliorating or delaying the onset of a disease, disorder or condition characterized by CD36 elevation in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising SPN10, or an analogue thereof, alone or in combination with one or more additional active agents, wherein SPN10 is the aromatic-cationic peptide H-L-Trp-L-Arg-L-Trp-L-Lys-NH 2 , or a tautomer, hydrate, solvate and/or pharmaceutically acceptable salt thereof. 
     
     
         10 . The method of  claim 9 , wherein the subject is diagnosed as having, suspected of having, or at risk of having atherosclerosis, inflammation, abnormal angiogenesis, abnormal lipid metabolism, abnormal removal of apoptotic cells, ischemia such as cerebral ischemia or myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's Disease, diabetes, diabetic nephropathy, or obesity. 
     
     
         11 .- 23 . (canceled) 
     
     
         24 . A conjugate comprising SPN10 conjugated to an aromatic-cationic peptide, wherein the aromatic-cationic peptide is selected from the group consisting of: H-2′6′-Dmt-D-Arg-Phe-Lys-NH 2 , H-Phe-D-Arg-Phe-Lys-NH 2 , or H-D-Arg-2′6′-Dmt-Lys-Phe-NH 2 , a peptide of Table A, Table 5, Table 6 or Table 7. 
     
     
         25 . The conjugate according to  claim 24 , wherein SPN10 is conjugated to the aromatic-cationic peptide by a linker. 
     
     
         26 . The conjugate according to  claim 24 , wherein SPN10 and the aromatic-cationic peptide are chemically bonded. 
     
     
         27 . The conjugate according to  claim 24 , wherein SPN10 and the aromatic-cationic peptide are physically bonded. 
     
     
         28 . The conjugate according to  claim 24 , wherein the aromatic-cationic peptide and SPN10 are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic-cationic peptide and SPN10. 
     
     
         29 . The conjugate according to  claim 28 , wherein the labile linkage comprises an ester linkage. 
     
     
         30 . A method for delivering an aromatic-cationic peptide and/or SPN10 to a cell, the method comprising contacting the cell with a conjugate, wherein the conjugate comprises SPN10 conjugated to an aromatic-cationic peptide, wherein the aromatic-cationic peptide is selected from the group consisting of: H-2′6′-Dmt-D-Arg-Phe-Lys-NH 2 , H-Phe-D-Arg-Phe-Lys-NH 2 , or H-D-Arg-2′6′-Dmt-Lys-Phe-NH 2 , a peptide of Table A, Table B, Table C, Table D or Table E. 
     
     
         31 . The method according  claim 30 , wherein SPN10 is conjugated to the aromatic-cationic peptide by a linker. 
     
     
         32 .- 33 . (canceled) 
     
     
         34 . The method according  claim 31 , wherein the aromatic-cationic peptide and SPN10 are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic-cationic peptide and SPN10. 
     
     
         35 . The method according  claim 34 , wherein the labile linkage comprises an ester linkage. 
     
     
         36 .- 56 . (canceled)